Although current antiretroviral therapy prolongs the life of HIV-infected individuals, it does not fully restore health. These drugs often have significant toxicities. Many individuals are not able to maintain long-term adherence necessary to maintain benefit. The drugs are expensive and are not available to most of the people globally who need them. To reverse the spread of the epidemic and to provide care for all, a fundamentally different approach is needed. One such approach would be to identify a means to cure HIV-infected people with a safe and scalable intervention. Despite complete or near complete inhibition of viral replication with standard therapies, replication-competent HIV persists indefinitely in all individuals. There are at least three mechanisms that contribute to this persistence: (1) maintenance of transcriptionally-silent proviral genomes within long-lived CD4+ T cells and myeloid cells, (2) proliferation of latently-infected cells with regeneration of a stable reservoir of slowly-dividing infected cells, and/or (3) tissue-based foci of viral replication and cell-to-cell spread that may be driven in part by local inflammatory responses. Our proposal has three broadly defined objectives that are aimed at understanding the nature of HIV persistence and reversing latency. First, we will define the anatomic and cellular distribution of replication-competent virus resides during long-term therapy. Second, we will investigate the host mechanisms that contribute to the establishment and maintenance of HIV latency, focusing on the role that cell-to-cell interactions have in silencing the transcription of integrated HIV DNA and/or otherwise maintaining its persistence. Third, we will develop and test (in non-human primates and in humans) targeted interventions aimed at reversing latency without broadly activating the immune system and/or DNA transcription. To address these objectives, we have assembled a group of investigators who have a long track record of successful collaboration, with each other and with others, and who believe that a cure will ultimately depend in part on modifying HIV-associated host responses that directly contribute to viral latency.